Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase III trial is studying the side effects of paclitaxel when given together with cisplatin or topotecan with or without bevacizumab and to compare how well they work in treating patients with stage IVB, recurrent, or persistent cervical cancer. Drugs used in chemotherapy, such as paclitaxel, cisplatin, and topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether paclitaxel is more effective when given together with cisplatin or topotecan with or without bevacizumab in treating patients with cervical cancer

Further Study Information

PRIMARY OBJECTIVES:

I. To determine whether the addition of bevacizumab to chemotherapy improves overall survival. Also to determine if a regimen involving paclitaxel and topotecan improves overall survival in comparison to a regimen involving cisplatin and paclitaxel. These regimens are to be evaluated in patients with stage IVB, recurrent, or persistent carcinoma of the cervix.

II. To determine and compare the frequency and severity of adverse events as assessed by CTCAE version 3.0 for the regimens administered on this study.

SECONDARY OBJECTIVES:

I. To estimate and compare the progression-free survival of patients treated by the regimens investigated on this study.

II. To estimate and compare the proportion of patients with tumor responses by the regimens investigated on this study.

TERTIARY OBJECTIVES:

I. To determine whether the addition of bevacizumab to chemotherapy, or the substitution of cisplatin with topotecan improve the health related quality of life (QOL) as measured by the FACT-Cx TOI and produce favorable toxicity profiles (with a particular focus on peripheral neuropathy as measured by the FACT/GOG-Ntx4 subscale and pain as measured by BPI single item).

II. To evaluate the impact of age, race, performance status, stage, histology, grade, disease site, prior chemotherapy with primary radiation, and time to recurrence on response rate, progression-free survival and overall survival of patients with metastatic/recurrent/persistent carcinoma of the cervix.

III. To determine the prevalence of active smoking in this cohort of recurrent cervical cancer patients.

IV. To estimate the extent of tobacco/nicotine dependence in the cohort. V. To determine if smoking is an independent risk factor for progression-free survival and overall survival in this population.

VI. To isolate, enumerate and characterize circulating tumor cells (CTC) recovered from blood drawn pre-cycle 1, pre-cycle 2 and pre-cycle 3 using the CTC-chip developed by the Massachusetts General Hospital (MGH) BioMEMS Resource Center and the MGH Cancer Center.

VII. To determine the association between CTC counts or characteristics and measures of clinical outcome.

VIII. To examine the association between angiogenesis markers in plasma (recovered from blood drawn pre-cycle 1, pre-cycle 2 and pre-cycle 3) and measures of clinical outcome.

IX. To evaluate the association between tumor markers of angiogenesis and hypoxia (using archival formalin-fixed and paraffin-embedded tumor tissue) and measures of clinical outcome.

X. To evaluate the association between single nucleotide polymorphisms (using DNA extracted from whole blood) and measures of clinical outcome as well as measures of quality of life such as chemotherapy toxicity.

XI. To examine the relationship(s) among the various biomarkers. XII. To develop an optimal prognostic model for progression-free survival and overall survival using clinical covariates, smoking status and the various biomarkers.

OUTLINE: This is a multicenter study. Patients are stratified according to disease status (recurrent/persistent disease vs primary stage IVB disease), GOG performance status (0 vs 1), and prior platinum therapy as a radiosensitizer (yes vs no). Patients are randomized to 1 of 4 treatment arms.

ARM I: Patients receive paclitaxel IV over 3 hours or 24 hours on day 1 and cisplatin IV on day 1 or 2.

ARM II: Patients receive paclitaxel IV over 3 hours or 24 hours on day 1 and cisplatin IV and bevacizumab IV over 30-90 minutes on day 1 or 2.

ARM III: Patients receive paclitaxel IV over 3 hours on day 1 and topotecan hydrochloride IV over 30 minutes on days 1-3.

ARM IV: Patients receive paclitaxel IV over 3 hours and bevacizumab IV over 30-90 minutes on day 1 and topotecan hydrochloride IV over 30 minutes on days 1-3.

In all arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients complete quality-of-life questionnaires, including the FACT-Cx TOI, FACT/GOG-Ntx4, and Brief Pain Inventory, at baseline, before courses 2 and 5, and at 6 and 9 months after course 1. Patients also complete a smoking questionnaire at baseline. After completion of study therapy, patients are followed every 3 months for 2 years and then every 6 months for 3 years.

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed carcinoma of the cervix, including any of the following subtypes:

• Squamous cell carcinoma

• Adenosquamous cell carcinoma

• Adenocarcinoma

• Primary stage IVB, recurrent, or persistent disease not amenable to curative treatment with surgery and/or radiotherapy

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan

• Biopsy confirmation required if target lesion(s) measures < 30 mm or if the treating physician determines it is clinically indicated

• Has ≥ 1 "target lesion" that can be used to assess response

• Tumors within a previously irradiated field are designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence ≥ 90 days following completion of radiotherapy

• No history or evidence of CNS disease, including primary brain tumor, brain metastases, or craniospinal metastases

• GOG performance status 0-1

• ANC ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Bilirubin ≤ 1.5 times normal

• SGOT ≤ 2.5 times normal

• Alkaline phosphatase ≤ 2.5 times normal

• PT/INR ≤ 1.5 (or in-range INR, if patient is on a stable dose of therapeutic warfarin for management of venous thrombosis, including pulmonary thromboembolus)

• PTT < 1.2 times upper limit of normal

• Serum creatinine normal OR creatinine clearance ≥ 60 mL/min

• Urine protein:creatinine ratio 1.0 mg/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment

• No active infection requiring antibiotics

• No significant traumatic injury within the past 28 days

• No serious non-healing wound, ulcer, or bone fracture

• Patients with granulating incisions healing by secondary intention are eligible provided there is no evidence of fascial dehiscence or infection AND the wound is examined weekly

• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 3-6 months

• Patients must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation

• No clinical symptoms or signs of gastrointestinal obstruction requiring parenteral hydration and/or nutrition

• No active bleeding or pathologic condition that carries a high risk of bleeding (e.g., known bleeding disorder, coagulopathy, or tumor involving major vessels)

• No seizures not controlled with standard medical therapy

• No cerebrovascular accident (i.e., stroke), transient ischemic attack, or subarachnoid hemorrhage within the past 6 months

• No clinically significant cardiovascular disease, including any of the following:

• Uncontrolled hypertension, defined as systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg

• Myocardial infarction or unstable angina within the past 6 months

• NYHA class II-IV congestive heart failure

• Serious cardiac arrhythmia requiring medication

• Atrial fibrillation allowed provided it is asymptomatic and ventricular rate is controlled

• Significant peripheral vascular disease (i.e., ≥ grade 2 peripheral vascular disease, as defined by NCI CTCAE v3.0 criteria)

• No bilateral hydronephrosis that cannot be alleviated by ureteral stents or percutaneous drainage

• No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies

• No other invasive malignancy within the past 5 years, except nonmelanoma skin cancer

• No other medical history or condition that, in the opinion of the investigator, would preclude study participation

• No peripheral neuropathy ≥ grade 2

• Recovered from all prior therapy

• No prior anti-cancer therapy that would preclude study therapy

• No prior anti-VEGF drugs, including bevacizumab

• No prior chemotherapy unless given concurrently with radiotherapy

• Prior paclitaxel and/or topotecan with radiotherapy not allowed

• At least 6 weeks since prior chemoradiotherapy

• At least 3 weeks since prior radiotherapy alone

• More than 28 days since prior major surgery or open biopsy

• More than 7 days since prior core biopsy

• No concurrent major surgery including, but not limited to, abdominal surgery prior to disease progression (e.g., colostomy or enterostomy reversal, interval or secondary cytoreductive surgery, or second-look surgery via laparotomy or laparoscopy)

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Krishnansu Tewari

Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00803062
Information obtained from ClinicalTrials.gov on March 12, 2013